p17 protein is known to play an important role in the pathogenesis of AIDS.
p17 is also known to represent the target of neutralizing antibodies directed against HIV-1 and high levels of anti-p17 antibodies are correlated with a slower progression towards AIDS. In addition to its support role in the virus replication, p17 exhibits several immunomodulating properties that could be significant within the context of the viral pathogenesis. p17 was indeed proven to increase the in vitro replication of HIV-1 and affects the activation and differentiation state, in addition to the proliferation ability, of the cells that constitute the target of the virus, such as CD4+ T lymphocytes, NK cells, monocytes, plasmacytoid dendritic cells. The ability of p17 to disrupt the physiological function of various cells of the immune system and to increase the production of pro-inflammatory molecules is very likely a mechanism exploited by the virus to escape the immune response and, at the same time, to create an environment that is more suitable for virus infection and replication. Recently, p17 was also observed to be exported outside the infected cells and it can be detected in the serum of HIV-1-infected patients, remaining in the lymph nodes, also in patients successfully treated with antiretrovirals and thus in the absence of virus replication. Such findings lead to believe that the mechanism of action observed in vitro is also possible in vivo.
Moreover, in previous studies the present inventors demonstrated that p17 protein exerts its biological activity directly by interacting with a specific receptor (p17R) expressed on the surface of several immunocompetent cells. The present inventors also identified an epitope in the N-terminal region of p17 that is involved in the binding with the receptor. The amino acid sequence of such epitope was identified and used for designing a synthetic peptide of 20 amino acids in length, designated as AT20, exemplary of the functional region of p17 from the HIV-1 BH10 isolate (HIV-1 B subtype). The synthetic peptide AT20 coupled with the Keyhole Limpet Hemocyanin (KLH) protein results in the generation of anti-p17 neutralizing antibodies capable of blocking the interaction p17/p17R and, accordingly, its biological activity.
In a subsequent study, the present inventors have also demonstrated that immunization of animals with the full-length p17 BH10 protein or with the synthetic peptide AT20-KLH causes the production of neutralizing sera capable of inhibiting the binding to p17R not only of the p17 BH10 protein but also of a series of African variants of such protein, identified as S75X, S85X, S92X and S012X, respectively (Fiorentini et al., Vaccine 26 (2008) 4758-4765). However, polyclonal antibodies exhibit several drawbacks. First of all, whenever it is desired to produce a polyclonal antibody it is necessary to resort to the immunization of animals. Secondly, the polyclonal antibodies produced at each immunization must be characterized and verified both for their binding and neutralizing properties and for their safety features.